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Molecular and Cellular Biology

Abstract LB-161: Metformin increases lipolytic metabolism and PEDF expression in prostate cancer cells

Akash Patnaik, Susan M. Wcislak, Lewis C. Cantley and Jennifer A. Doll
Akash Patnaik
1Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA
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Susan M. Wcislak
2University of Wisconsin Milwaukee, Milwaukee, WI
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Lewis C. Cantley
3Department of Systems Biology, Beth Israel Deaconess Medical Center, Boston, MA
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Jennifer A. Doll
2University of Wisconsin Milwaukee, Milwaukee, WI
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DOI: 10.1158/1538-7445.AM2012-LB-161 Published April 2012
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Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Abstract

Obesity increases the risk of prostate cancer (PCa) progression; however, the mechanism remains unclear. Obesity results in metabolic dysfunction, including increases in circulating and tissue lipid levels. A common sequela of obesity is Type II diabetes, and some studies suggest that PCa patients on the antidiabetic drug, metformin, have a reduced PCa risk. The antitumor mechanism of metformin is largely unknown. Metformin exerts its antidiabetic function via AMPK activation-dependent inhibition of hepatic gluconeogenesis, with secondary decrease in serum insulin/IGF-1 levels that may represent an indirect mechanism for its proposed antitumor effects. Previous studies have shown that metformin directly inhibits PCa cell proliferation and cyclin D1 expression in vitro. Expression of pigment epithelium-derived factor (PEDF), a potent angiogenesis inhibitor, is decreased in PCa tissues, and PEDF inhibits PCa cell proliferation. Interestingly, PEDF knockout mice have defects in lipid metabolism and develop prostate hyperplasia, so we hypothesized that metformin's antitumor mechanism could be mediated, in part, through regulation of PEDF expression and lipolytic metabolism. To simulate obesity-induced cellular triglyceride (TG) accumulation, we treated cells with oleic acid (OA, 1.0 mM) ± PEDF (10 nM) or metformin (5 mM). Proliferation (cell count or MTT assay) and lipid content (TG isolation) were quantified, and lipid and protein were assessed by lipid staining and immunocytochemistry or Western blot, respectively. In androgen-insensitive PCa cells (PC-3 and DU145), OA treatment promoted TG accumulation, cyclin D1 expression and proliferation, with increased expression of lipid droplet-associated proteins, adipose triglyceride lipase (ATGL) and CGI-58, and conversely suppressed PEDF expression. Furthermore, PEDF treatment decreased basal TG levels (32.89 ± 1.0 control vs. 17.3 ± 0.6 in PEDF; P<0.0002) and suppressed OA-induced TG accumulation (130.33 ± 1.2 μg/1x106 cells in OA vs. 72.92 ± 3.5 OA + PEDF; P<0.0002) and proliferation (P<0.05), concomitantly decreasing ATGL and CGI-58 expression. Interestingly, metformin blocked OA-induced proliferation (P<0.02), decreased ATGL and CGI-58 expression, and increased PEDF expression. When free glycerol release was quantified as a measure of TG lipolysis, both metformin and PEDF increased PCa cell TG turnover compared to control cells (P<0.05). These data suggest that metformin exerts its anti-proliferative effect on PCa cells, in part, through upregulation of lipolytic metabolism via increased PEDF expression. These data provide a novel pharmacodynamic biomarker for mechanistic studies in patients, and platform for rational design of “personalized” cancer therapies targeting altered lipid metabolism in obesity-induced cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-161. doi:1538-7445.AM2012-LB-161

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Cancer Research: 72 (8 Supplement)
April 2012
Volume 72, Issue 8 Supplement
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Abstract LB-161: Metformin increases lipolytic metabolism and PEDF expression in prostate cancer cells
Akash Patnaik, Susan M. Wcislak, Lewis C. Cantley and Jennifer A. Doll
Cancer Res April 15 2012 (72) (8 Supplement) LB-161; DOI: 10.1158/1538-7445.AM2012-LB-161

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Abstract LB-161: Metformin increases lipolytic metabolism and PEDF expression in prostate cancer cells
Akash Patnaik, Susan M. Wcislak, Lewis C. Cantley and Jennifer A. Doll
Cancer Res April 15 2012 (72) (8 Supplement) LB-161; DOI: 10.1158/1538-7445.AM2012-LB-161
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Cancer Research Online ISSN: 1538-7445
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